Synthesis of vitamin b6



Patented Sept. 27, 1949 2,483,137 SENTH S S F B6 Stanton A. Harris, Westfield, N.

Inc Rahway,

Merck .& Co t of c J e e No Drawing. Application 5., assignor to J a corpora= January 10, 1946,

Serial No. 40,391

6 Claims (01. goon-297.5)

This invention relates to a process for the preparation of novel chemical compounds; in a par.- ticular sense it is concerned with the preparation of intermediates useful in the synthesis of vitamin B6 (2 methyl 3 hydroxyijrdflhydroxymethyl) pyridine) 1 This application is a con nuation-in-par o the .co-pending application by the same inventor Serial No. 428,080, filed January 2%, 1942 issued June 17, i as Patent No. 231 249 whi h s a division of Serial No. 293,131, filed September 1, 1933, issued February 10, 1942, as Patent No. ,273, 9

qc d ns to n m o iment f h p e t nvention amino compounds of the formula:

CHzOR z lliNHZ N wh n R. is alkyl. e y nd ra wh n iatotized with nitrous acid or a nitrite under acidic conditions yield compounds of the formula:

on o

HO CHzOH wherein R is as above. The hydrohalide salts of these compounds can be hydrolyzed to obtain vitamin B6 hydrohalide.

In general, the process Example CHzOCZHB CHzNHz HONO H0 1130 N .2HO1 N 300 grams of 2-methyl-3-amino-4-ethoxymethyl-5-aminomethylpyridine dihydrochloride are dissolved in 430 cc. of water, neutralized with CHzOCgHs H N CH2 OH HsC ' and filtered. ith th 2 odium hydrox de ph n lphth n and 5 5 sodium nitrit re add d T is Solution cede-d slow t see: f ho 9 0-. 2 N ulfuric. acid with t insi an. immed ate o ni ro n fo lo ed the ioi-matic ic a 1. 1 v v p. tion is heated for an additional 15 minutes, ti ated wit u t en u h ur a t deccmros th ss i ous acid, c oled nd ne tr ized o p3 w th odium h droxide solu ion. usin bromothymol blue out. ind cat r The slightly reddish solution is under s ar to eeara At thi point a b ade o l yer is i l ed which contains most of the desired prodt is sso ved n 2% ie, aceton filtered r m separated sod m l ah;z a d evapo ated o d nes Th r sidue is en re ol d in 2% ie, of ac tone, filter d from t e Sep ated se ium ch o ide an e por ted to d yness. It is ak n up a hird time i 2% kg. o one, f l tered from an insoluble material and diluted with an equal volume of ether, whereupon a dark; red oi sena t s, The supern t nt liquid. is d ant d aid of e rl- 'afl n (an acti vated charcoal). The slightly yellowsolution is evas rat l to y e o 2 me h l- -hydrexr 4 e ethex m l -hy mXy etl pyrh d ie is i2 0, or about 50% of the theory.

concentrated diminished pressure until sodium sulfate 4 al mat rial can. be ob ne fmmth p pitated oil and by elution of the charcoal with iso tatic-t OH'zOCzHa 0112002 5 HQ: on on H01 no on on me E o NHHCI' Fifty grams of the above material are dissolved in 500 cc. of acetone and treated with dry hydrogen chloride until the solution is acid to wet Congo paper whereupon a brown colored hydrochloride crystallizes out. The addition of ether yields some additional crystals. These crystals are twice recrystallized by dissolving in a minimum of alcohol and adding an equal volume of acetone and filtering with the aid of carboraflin. The yield is 25.3 g. or 21.5% of the theory based on the original diamine; M. P. -136 C. Additional crystals may be obtained from the mother liquors.

CHgOCzHn H30 N .HCI

CHzOH 0.4 gram methyl--hydroxymethylpyridine hydrochloride is dissolved in 40 cc. of water containing 2 cc. of 2.5 N hydrochloric acid and the solution is heated in a bomb tube at 155-160 C. for three hours. After cooling, the tube is opened and the contents are evaporated to dryness on a steam bath under reduced pressure. The crystalline residue is recrystallized from 95% alcohol, using charcoal for clarification; melting point 206-20'l 0., mixed melting point with analytically pure vitamin B6 shows no depression. The yield is 2.81 grams or 80% of theory.

In like manner 2-methyl-3-amino-4-benzyloxyr'nethyl-5-aminomethylpyridine is treated with nitrous acid or a nitrite under acid conditions to yield z-methyl-3-hydroxy-4-benzyloxymethyl-5- hydroxymethylpyridine. The hydrohalide salt of the latter compound is hydrolyzed and vitamin B6 hydrohalide is recovered.

2-methyl-3-amino-4-phenoxymethyl-5-aminomethylpyridine is treated with nitrous acid or a nitrite under acidic conditions to yield 2-methyl- 3-aminc-4-phenoxymethyl-5-hydroxymethylpyridine. The hydrohalide salt of the latter compound is hydrolyzed and vitamin B6 hydrohalide is recovered.

Modifications may be made in carrying out the present invention without departing from the spirit and scope thereof, and I am to be limited only by the appended claims.

I claim:

1. In the synthesis of vitamin B6, the steps which comprise diazotizing and hydrolyzing 2- methyl-S-aminol-alkoxymethyl- 5 -arninometh ylpyridine dihydrohalide, recovering the Z-methyl-3-hydroXy-4-alkoxymethyl-5-hydroxymethylpyridine thus formed, reacting the latter compound with a hydrogen halide in the presence of an organic solvent, recovering the 2-methyl-3- hydroxy-e-alkozxymethyl- 5 hydroxymethylpyridine hydrohalide thus formed and hydrolyzing the latter compound with a dilute acid solution at a temperature and pressure sufficient to form Z-methyl-3-hydroxy-4,5-di(hydroxymethyl) pyridine hydrohalide.

2. In the synthesis of vitamin Be, the steps which comprise reacting an aqueous solution of 2-rnethyl-3-aminol-alkoxymethyl-5-aminomethylpyridine with nitrous acid in acid solution, recovering the 2-methyl-3-hydroxy-4-alkoxymethyl-S-hydroxymethylpyridine thus formed, reacting the latter compound with hydrogen halide in the presence of an organic solvent, recovering the 2-methyl-3-hydroxyl-alkoxymethyl-5-hydroxymethylpyridine hydrohalide thus formed, reacting the latter compound with a of 2-methyl-3-hydroxy-4-ethoxy- 4 dilute hydrochloric acid solution for a time and at a temperature and pressure sufficient to effect hydrolysis, and recovering the 2-methyl-3-hydroxy-4,5-di(hydroxymethyl) pyridine hydrochloride thus formed.

3. In the synthesis of vitamin Be, the steps which comprise neutralizing an aqueous solution of 2-methyl-3-amino-4-ethoxymethyl-5-aminomethylpyridine dihydrochloride with sodium hydroxide, adding sodium nitrite, pouring the solution into hot sulfuric acid, recovering the Z-methyl-3-hydroxy-4-ethoxymethyl-5-hydrqxymethylpyridine thus formed, dissolving the 2-methy1-3- hydroxy-d-ethoxymethyh 5 -hydroxymethylpyridine in acetone, reacting said acetone solution with dry hydrogen chloride, to precipitate the 2-methyl-3-hydroxy-4-ethoxymethyl-5-hydroxymethylpyridine hydrochloride thus formed, reacting the latter compound with dilute hydrochloric acid solution in a closed vessel for about three hours at about 160 C., and recovering the Z-methyl-3-hydroxy-4,5-di(hydroxymethyl) pyridine hydrochloride thus formed.

4. In the synthesis of vitamin B6, the step which comprises diazotizing and hydrolyzing 2- methyl-3-amino-4r-alkoxymethyl- 5 -aminomethylpyridine dihydrohalide and recovering the Z-methyh 3-hydroxy-l-alkoxymethyl-5 -hydroxymethylpyridine thus formed.

5. In the synthesis of vitamin Be, the step which comprises reacting an aqueous solution of 2-methyl-3-aminoi-alkoxymethyl-5-aminomethylpyridine with sodium nitrite in the presence of a hot mineral acid and recovering the 2 -methyl-3-hydroxy-4 alkoXymethyl-5 -hydroxymethylpyridine thus formed.

6. In the synthesis of vitamin B6, the step which comprises reacting 2-methyl-3-hydroxyd-alkoxymethyl-5-hydroxymethylpyridine hydrochloride with a dilute hydrochloric acid solution for a, time and at a temperature and pressure sufiicient to effect hydrolysis and recovering the 2-methy1-3-hydroXy-4,5-di(hydroxymethyl) pyridine hydrochloride thus formed.

STANTON A. HARRIS.

REFERENCES CITED The following references are of record in the file of this patent:

FOREIGN PATENTS Number Country Date 543,615 Great Britain Mar. 6, 1942 OTHER REFERENCES J. A. C. S. (1941) V01. 63, pages 3363-3367. 

